The theme of our Program Project is the molecular genetic analysis of the metabolic syndrome, particularly hypertriglyceridemia, insulin resistance and obesity. Our approach is to use mouse and human homology at the genetic, physiological, pathological and biochemical levels. During the current grant period, we have utilized this approach to identify three genes relevant to the metabolic syndrome-Txnip (thioredoxin interacting protein), lipin, and USF1 (upstream transcription factor 1). Txnip and lipin were identified via positional cloning in mouse models of combined hyperlipidemia and lipodystrophy, respectively, and function in fundamental processes such as adipose tissue development, and glucose and lipid homeostasis. USF1 is the first major gene identified for familial combined hyperlipidemia (FCHL), the most prevalent familial dyslipidemia predisposing to coronary heart disease. USF1 was identified by genetic analysis of families from the Finnish isolate, and we have recently confirmed its role in FCHL in three additional populations. We propose 4 Projects and 4 Cores that will interact closely. We will continue the strategy of using the mouse model and multiple human populations to search for additional genes and to characterize the metabolic dysregulation underlying the metabolic syndrome. Dr. Wong's Project will investigate mechanisms by which Txnip and apolipoprotein A-II function in glucose and lipid metabolism, identify the Hyplip2 gene which contributes to combined hyperlipidemia and atherosclerosis, and investigate USF1 function in mouse models. Dr. Pajukanta's Project will analyze multiple human FCHL populations to identify additional genes contributing to this disorder. Dr. Aldons'Project will isolate the gene causing combined lipase deficiency in a mouse model, further explore the structure of lipase enzymes, and determine the contribution of lipase genetic polymorphisms to insulin resistance in the metabolic syndrome. Dr. Reue's Project will further elucidate the physiolgical and molecular function of lipin in adipocyte differentiation and energy metabolism and evaluate its role in human disease. These projects will interact closely with Cores providing expertise and resources for Lipoprotein Analysis and Biochemistry, Genotyping and Sequencing, and Statistical Analysis.